Clinical significance of extrapyramidal signs in patients with cirrhosis

doi:10.1016/j.jhep.2004.12.030

Journal of Hepatology

Volume 42, Issue 5, May 2005, Pages 659-665

https://doi.org/10.1016/j.jhep.2004.12.030 Get rights and content

Background/Aims

Extrapyramidal signs have been described in cirrhosis and there is little information about their clinical significance. The aims of this study have been to investigate the relationship between extrapyramidal signs and cognitive impairment, and what is their influence on quality of life.

Methods

46 patients with cirrhosis were evaluated for cognitive impairment with psychometric tests (Trail-Making Test part A, Grooved-Pegboard, Block-Design, Oral Symbol Digit and Stroop Test) and cognitive evoked potentials (P300). Extrapyramidal signs were evaluated using the UPDRS scale. Health-related quality of life (HRQL) was measured using SF-36 scale and the Chronic Liver Disease Questionnaire (CLDQ).

Results

Twenty-two patients had extrapyramidal signs, and these patients scored worse in all psychometric tests, except Block-Design. Patients with extrapyramidal signs also showed a longer P300 latency. Moreover, patients with extrapyramidal signs had the worst score in all the HRQL scales used. A multivariate analysis disclosed that the only variable showing an independent relationship to the mental component summary of SF-36 and with CLDQ was UPDRS score.

Conclusions

We have found a clear relationship between the presence of extrapyramidal signs and cognitive impairment. Moreover, patients with extrapyramidal signs have worse scores in quality of life scales.

Introduction

The pathophysiology of hepatic encephalopathy is still not well understood, despite much research that has been carried out during the last 50 years. Neurological manifestations are considered to result from a derangement of multiple neurotransmitter systems. Accumulation of several neurotoxic substances has been reported [1] and it is likely that many of them contribute to the pathogenesis of hepatic encephalopathy.

Patients with cirrhosis frequently show mild extrapyramidal signs secondary to alterations of basal ganglia circuitry [2]. Basal ganglia impairment is mainly related to manganese deposition in this cerebral structure [3], [4], [5], [6], [7], [8], [9], [10], [11], but other metabolic abnormalities have been found in basal ganglia in cirrhosis: a reduced glucose consumption [12], and an increased glutamine-glutamate peak in the spectroscopic study, compared with other brain regions [13], [14]. Furthermore, it has been shown that patients with cirrhosis have an increased dopamine metabolism in basal ganglia [15], with a decreased D2 dopamine receptor density [16] and this may be implicated in the pathogenesis of both motor and cognitive alterations frequently observed in cirrhotic patients [4], [7], [17]. However, there is little information about the clinical significance of extrapyramidal signs associated with cirrhosis, and it is not known if the existence of this neurological signs influences the daily-life activities of patients with cirrhosis.

Patients with advanced cirrhosis may show a mild cognitive impairment, what has been called minimal hepatic encephalopathy (MHE). We have previously shown the existence of a link between these two mild neurological alterations in cirrhosis [18], and this finding may be explained by the influence of extrapyramidal manifestations on performance of manual neuropsychological tests used for the diagnosis of MHE or by a real pathophysiological relationship between both disorders [18].

The aims of this study have been, first, to investigate the possibility of a relationship between the impairment of basal ganglia, expressed as the presence of extrapyramidal signs, and cognitive disturbance, evaluated by tests that are not influenced by motor alterations. A second objective is to know what is the clinical significance of the extrapyramidal signs and its possible influence on quality of life.

Section snippets

Patients

Between January 2001 and September 2002, a group of 46 consecutive patients in whom the diagnosis of cirrhosis was made on the grounds of liver biopsy (21 patients) or findings recorded on physical examination, results of laboratory tests, and imaging studies at Hospital General Universitario de Alicante were included in this cross-sectional study. The cause of cirrhosis was alcohol in 26 patients, HCV infection in 16, HBV infection in 1 patient and other causes in 3 patients. All the patients

Results

The study population consisted of 32 men and 14 women with a mean age of 58.8 yr (range 41–73 yr). Seventeen patients were in A grade of Child-Pugh classification, 19 in B grade and 10 in C grade, and the mean Child-Pugh score was 7.5±2.1 (range 5–12). Two patients had received a transjugular intrahepatic portosystemic shunt. The clinical characteristics of patients are shown in Table 1.

MHE was diagnosed in 22 patients (47.8%), using the formerly described criteria. Nineteen of them (86%) showed

Discussion

This study shows that cirrhotic patients with extrapyramidal signs have a greater cognitive impairment than patients without this neurological problem. The existence of extrapyramidal signs affects the performance of both manual neuropsychological tests and those that are not influenced by motor impairment, such as non-manual neuropsychological tests. Cirrhotic patients with extrapyramidal signs have also cognitive impairment as demonstrated by neurophysiological methods, using cognitive evoked

Acknowledgements

Financial support. Supported in part by a grant from Instituto de Salud Carlos III, Madrid, Spain (Convocatoria de Redes Temáticas) G03/155 and C03/02.

References (40)

D. Krieger et al.
Manganese and chronic hepatic encephalopathy
Lancet
(1995)
L. Spahr et al.
Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms
Hepatology
(1996)
G. Pomier-Layrargues et al.
Increased manganese concentrations in pallidum of cirrhotic patients
Lancet
(1995)
C. Rose et al.
Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction
Gastroenterology
(1999)
V.L. Rao et al.
Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy
Brain Res
(1993)
D.D. Mousseau et al.
Selective loss of pallidal dopamine D2 receptor density in hepatic encephalopathy
Neurosci Lett
(1993)
S. Montes et al.
Striatal manganese accumulation induces changes in dopamine metabolism in the cirrhotic rat
Brain Res
(2001)
R. Jover et al.
Minimal hepatic encephalopathy and extrapyramidal signs in patients with cirrhosis
Am J Gastroenterol
(2003)
M.F. Folstein et al.
‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975)
L. Spahr et al.
Magnetic resonance imaging and proton spectroscopic alterations correlate with parkinsonian signs in patients with cirrhosis
Gastroenterology
(2000)

S. Krieger et al.

Neuropsychiatric profile and hyperintense globus pallidus on T1-weighted magnetic resonance images in liver cirrhosis

Gastroenterology

(1996)

P. Brown et al.

What do the basal ganglia do?

Lancet

(1998)

A.T. Blei et al.

Hepatic encephalopathy

Am J Gastroenterol

(2001)

N.J. Shah et al.

Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging

Hepatology

(2003)

G. Marchesini et al.

Factors associated with poor health-related quality of life of patients with cirrhosis

Gastroenterology

(2001)

R.F. Butterworth

The neurobiology of hepatic encephalopathy

Semin Liver Dis

(1996)

P.R. Burkhard et al.

Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration

Arch Neurol

(2003)

G.P. Layrargues et al.

Role of manganese in the pathogenesis of portal-systemic encephalopathy

Metab Brain Dis

(1998)

L. Spahr et al.

Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy

Metab Brain Dis

(2002)

R.F. Butterworth et al.

Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy

Metab Brain Dis

(1995)

Cited by (29)

Altered motor cortical plasticity in patients with hepatic encephalopathy: A paired associative stimulation study
2021, Clinical Neurophysiology
Citation Excerpt :
This change of transduction pathways alters glutamatergic neurotransmission in multiple brain regions, which potentially leads to the wide palette of symptoms in HE. For example, hypokinesia and locomotion impairment in HE were linked to changes in the basal ganglia-thalamo-cortical loop (Cauli et al., 2009; Jover et al., 2005), and impaired motor learning in HE had been associated with alteration of the glutamate-NO-cGMP pathway in the cerebellum (Cauli et al., 2007; Erceg et al., 2005). A schematic of the proposed interplay between hyperammonemia and glutamatergic neurotransmission is depicted in Fig. 5.
Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE.
23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups.
MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity.
Our study revealed reduced synaptic plasticity of the primary motor cortex in HE.
Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.
A discussion of new-onset extrapyramidal syndrome without tremor and neuroimaging signs of encephalopathy following hepatic cirrhosis
2019, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Citation Excerpt :
In the 18 re-evaluated patients, there was an increase in the score of the UPDRS. Patients with extrapyramidal signs persisted with worse scores in several items of the SF-36 scale and the CLDQ [8]. So, the presence of extrapyramidal signs in patients with liver cirrhosis predicts the development of HE and a bad influence on quality of life.
Liver cirrhosis can cause neurological, extrapyramidal-type disorders, such as stiffness, bradykinesia, tremor, confusion, depression. Cirrhotic extrapyramidal syndrome can worsen clinically, leading to encephalopathy, which in the most severe cases leads to coma. Brain MRI is able to highlight the extrapyramidal signs, through the presence of hyperintensity areas at the basal ganglia. In addition, extrapyramidal symptoms appear already in the metabolic compensation phase. We describe the case of a 50-year-old male, suffering from new-onset extrapyramidal syndrome, secondary to alcoholic hepatic cirrhosis, diagnosed seven years before. The case is singular for some features: the late-onset of the extrapyramidal syndrome, the absence of tremor, and especially the lack of neuroimaging findings such as MRI hyperintense areas along the basal ganglia.
We hypothesize a mechanism of metabolic compensation, which would be responsible for the late appearance of the extrapyramidal syndrome and the lack of signs of encephalopathy in brain MRI.
The lack of tremor is less clear, because it is a constant symptom of extrapyramidal pathology, and it is unusual that it is lacking as a symptom, after so many years.
Targeted upregulation of uncoupling protein 2 within the basal ganglia output structure ameliorates dyskinesia after severe liver failure
2018, Free Radical Biology and Medicine
Citation Excerpt :
Apart from HE, there is growing evidence that oxidative stress is closely related to a series of neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis [4–6]. Hypokinesia, or decreased behavioral or locomotor activity, constitutes a major motoric alteration in HE patients, which is attributed to the alterations of the neuronal circuits between the basal ganglia and the prefrontal cortex (PFC) [7]. Substantia nigra pars reticulata (SNr) consists of GABA-containing projection neurons and functions as a relay area for basal ganglia output [8].
Impaired motor function, due to the dysfunction of the basal ganglia, is the most common syndrome of hepatic encephalopathy (HE), and its etiology remains poorly understood. Neural oxidative stress is shown to be the major cellular defects contributing to HE pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neurological disorders. We explored the neuroprotective role of UCP2 within the substantia nigra pars reticulate (SNr), the output structure of the basal ganglia, in HE. The toxin thioacetamide (TAA) induced HE mice showed hypolocomotion, which was associated with decreased ATP levels and loss of antioxidant substances SOD and GSH within the SNr. Stable overexpression of UCP2 via AAV-UCP2 under the control of the UCP2 promoter in bilateral SNr preserved local ATP level, increased antioxidant substances, and ameliorated locomotion defects after severe liver failure. Contrary to UCP2 overexpression, targeted knockdown of UCP2 within bilateral SNr via AAV-UCP2 shRNA exacerbated the impaired mitochondrial dysfunction and hypokinesia in HE mice. The modulatory effects of UCP2 was due to mediation of K⁺-Cl⁻ cotransporter-2 (KCC2) expression on GABAergic neurons of SNr. Taken together, our results demonstrate that UCP2 exerts a neural protective role at the subcortical level by increasing the resistance of neurons to oxidative stress, which may offer a novel therapeutic target for the treatment of motor dysfunction diseases.
Deep sedation with propofol does not precipitate hepatic encephalopathy during elective upper endoscopy
2009, Gastrointestinal Endoscopy
Citation Excerpt :
However, a significant proportion of patients who appear normal on clinical examination exhibit quantifiable neuropsychologic deficits, a condition termed MHE. MHE is a prevalent and silent complication of cirrhosis that affects quality of life,20 is related to motor impairment,21,22 and is a predictor of traffic infractions and accidents.20,23 The majority of patients with cirrhosis and suspected portal hypertension who receive endoscopic procedures have evidence of MHE.1
The risk of hepatic encephalopathy (HE) precipitated by propofol has not been established.
To know whether the use of propofol for endoscopy in patients with cirrhosis induces minimal or overt HE.
A cohort study.
A tertiary-referral university hospital endoscopy unit.
Patients with cirrhosis who received an endoscopy with propofol sedation. We excluded patients with clinical HE. A group of patients without liver disease was included to compare the incidence of adverse effects.
Minimal HE (MHE) was diagnosed by using the psychometric hepatic encephalopathy score (PHES) battery of psychometric tests. Cognitive status before and 1 hour after the endoscopy was evaluated by measuring the critical flicker frequency (CFF).
Overt and minimal HE.
Twenty patients with cirrhosis and 20 patients without cirrhosis were included. There were no differences between groups in the incidence of adverse effects. Thirteen patients (65%) had MHE before the endoscopy. No patient developed overt HE after sedation. We did not observe differences in CFF before and after sedation in patients without MHE: median (25th-75th percentile), 40.8 Hz (37.1-46.0 Hz) versus 41.1 Hz (36.0-44.3 Hz), P = .8). None of the patients who were without MHE showed a decrease in the CFF under the cutoff of 39 Hz after sedation. There were not significant changes in CFF before and after propofol sedation in patients previously diagnosed of MHE: median (25th-75th percentile), 40.6 Hz (36.8-49.1 Hz) versus 42.7 Hz (36.8-52.4 Hz), P = .08.
A small number of patients were included in the study.
The use of propofol in the sedation of patients with cirrhosis during endoscopic procedures does not precipitate minimal or overt HE.
Hypolocomotion in rats with chronic liver failure is due to increased glutamate and activation of metabotropic glutamate receptors in substantia nigra
2006, Journal of Hepatology
Patients with hepatic encephalopathy show altered motor function, psychomotor slowing and hypokinesia. The underlying mechanisms remain unclear. This work’s aims were: (1) to analyse in rats with chronic liver failure due to portacaval shunt (PCS) the neurochemical alterations in the basal ganglia–thalamus–cortex circuits; (2) to correlate these alterations with those in motor function and (3) to normalize motor activity of PCS rats by pharmacological means.
Extracellular neurotransmitters levels were analysed by in vivo brain microdialysys. Motor activity was determined by counting crossings in open field.
Extracellular glutamate is increased in substantia nigra pars reticulata (SNr) of PCS rats. Blocking metabotropic receptor 1 (mGluR1) in SNr normalizes motor activity in PCS rats. In ventro-medial thalamus of PCS rats GABA is increased and it is normalized by blocking mGluR1 in SNr. Blocking mGluR1 in SNr increases and mGluR1 activation reduces glutamate in motor cortex and motor activity.
Increased extracellular glutamate and activation of mGluR1 in SNr are responsible for reduced motor activity in rats with chronic liver failure. Blocking mGluR1 in SNr normalizes motor activity in PCS rats, suggesting that, under appropriate conditions, similar treatments could be useful to treat the psychomotor slowing and hypokinesia in patients with hepatic encephalopathy.
The Protective Effect of Ultrasonicated Ginseng Berry Extract on Rat Hepatic Encephalopathy Model Induced by Mild Bile Duct Ligation
2024, SSRN

View all citing articles on Scopus

View full text

Clinical significance of extrapyramidal signs in patients with cirrhosis

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgements

Lancet

Hepatology

Lancet

Gastroenterology

Brain Res

Neurosci Lett

Brain Res

Am J Gastroenterol

J Psychiatr Res

Gastroenterology

Gastroenterology

Lancet

Am J Gastroenterol

Hepatology

Gastroenterology

The neurobiology of hepatic encephalopathy

Semin Liver Dis

Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration

Arch Neurol

Role of manganese in the pathogenesis of portal-systemic encephalopathy

Metab Brain Dis

Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy

Metab Brain Dis

Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy

Metab Brain Dis